1. Field of the Invention
The invention generally relates to the field of immunology.
2. Background Art
Mycobacterium are known to cause serious diseases in mammals, e.g., tuberculosis, Hansen's disease, leprosy, pulmonary disease resembling tuberculosis, lymphadenitis, skin disease, or disseminated disease. A third of the world's population is infected with Mycobacterium tuberculosis, and 2 million people die from tuberculosis (TB) every year even though the bacille Calmette Guérin (BCG) vaccine has been available for more than 75 years. Hoft D F, Lancet 372: 164-175 (2008). Tuberculosis is currently the second highest cause of death from an infectious disease worldwide, after HIV/AIDS. Young D B et al., Journal of Clinical Investigation 118: 1255-1265 (2008).
Several studies suggest that both MHC class I- and II-restricted T cells are required for effective control of M. tuberculosis infection. Mogues T et al., J Exp Med 193: 271-280 (2001) and Flynn J L et al., Proc Natl Acad Sci USA 89: 12013-12017 (1992). However, mice that are deficient in the lipid-antigen presenting molecule, CD1d, are not more susceptible than wild-type mice to M. tuberculosis infection, indicating that CD1d-restricted NKT cells are not absolutely required for protective immunity. Behar S M et al., J Exp Med 189: 1973-1980 (1999). Natural killer T (NKT) cells represent a subset of T lymphocytes expressing both T-cell receptor and NK-cell receptor, and play a role in bridging innate immunity to adaptive immunity. Kronenberg M and Gapin L, Nat Rev Immunol 2: 557-568 (2002). Upon activation, NKT cells can have a pronounced impact on early and delayed immunity to various pathogens, including L. monocytogenes, M. tuberculosis and Leishmania major. Kronenberg (2002); Behar S M and Porcelli S A, Curr Top Microbiol Immunol 314: 215-250 (2007); Emoto M et al., Eur J Imtnunol 29: 650-659 (1999); Ishikawa H et al., Int Immunol 12: 1267-1274 (2000); and Ranson T et al., J Immunol 175: 1137-1144 (2005). NKT cell activation has been reported to lead to enhanced CD4 and CD8 T cell responses, and to induce dendritic cell maturation. Nishimura T et al., Int Immunol 12: 987-994 (2000) and Silk J D et al., J Clin Invest 114: 1800-1811 (2004).
Unlike conventional T cells that recognize MHC-bound peptides, NKT cells are specific for lipid antigens presented by the MHC class I-like protein CD1d. Several glycolipid antigens, including self-derived and bacterial-derived glycolipids, which can be presented by CD1d to activate NKT cells, have been identified to date. Tsuji M Cell Mol Life Sci 63: 1889-1898 (2006). NKT cells that have T-cell receptors with invariant Vα14-Jα18 rearrangements (iNKT cells) possess reactivity to a glycosphingolipid, α-galactosylceramide (αGalCer), when presented by CD1d. Kronenberg M and Gapin L, Nat Rev Immunol 2: 557-568 (2002); Kronenberg M, Annu Rev Immunol 23: 877-900 (2005). Recent studies have shown that vaccines against Plasmodia, Leishmania donovanii, Listeria monocytogenes and HIV could be improved by activating iNKT cells through co-administration of αGalCer as an adjuvant. Gonzalez-Aseguinolaza G et al., J Exp Mal 195: 617-624 (2002); Dondji B et al., European Journal of Immunology 38: 706-719 (2008); Huang Y X et al., Vaccine 26: 1807-1816 (2008); and Enomoto N et al., FEMS Immunol Med Microbiol 51: 350-362 (2007).
As a therapeutic, αGalCer has been shown to reduce malarial parasite load in mice and prolong the survival of M. tuberculosis infected mice. Gonzalez-Aseguinolaza G et al., Proc Natl Acad Sci USA 97: 8461-8466 (2000); Chackerian A et al., Infection and Immunity 70: 6302-6309 (2002). Thus, although CD1d-restricted T cells are not absolutely required for optimum immunity, their specific activation enhances host resistance to infectious diseases.
A single injection of αGalCer in mice induces a cytokine storm in the serum resulting in secretion of IFNγ, IL-12 and IL-4. Fujii S et al., Immunol Rev 220: 183-198 (2007). Stimulation of CD1d-restricted iNKT cells by αGalCer also leads to rapid activation of NK cells, dendritic cells, B cells, and conventional T cells. Nishimura T et al., Int Immunol 12: 987-994 (2000); Kitamura H et al., J Exp Med 189: 1121-1128 (1999); Fujii S et al., J Exp Med 198: 267-279 (2003). iNKT cells produce large amounts of IFNγ and the production requires direct contact between iNKT cells and DCs through CD40-CD40 ligand interactions. Nishimura T et al., Int Immunol 12: 987-994 (2000). IFNγ produced by iNKT cells has been shown to have a critical role in the antimetastatic effect of αGalCer in murine tumor models. Hayakawa Y et al., Eur J Immunol 31: 1720-1727 (2001); Smyth M J et al., Blood 99: 1259-1266 (2002). Thus, it has been proposed that activation of iNKT cells can modulate adaptive immune responses by influencing the early cytokine environment.
Recently, a C-glycoside analogue of αGalCer known as the α-C-GalCer has been established as a predominant Th1 skewing compound which has a superior anti-tumor and anti-malarial activity as compared to αGalCer in mice. This compound also induces higher levels of Th1 cytokines IL-12 and IFNγ in mice. Schmieg J et al., Journal of Experimental Medicine 198: 1631-1641 (2003). It has been established that these two cytokines, IL-12 and IFNγ, are essential for control of TB in mice and humans. Freidag B L et al., Infect Immun 68: 2948-2953 (2000).
Very few studies exist on the use of adjuvants with BCG vaccine in the mouse model against tuberculosis. One such study reported an enhanced protection against M. tuberculosis challenge when CpG ODN was used along with BCG vaccination. Freidag B L et al., Infect Immun 68: 2948-2953 (2000). Most of the earlier studies on the adjuvant effect of αGalCer with vaccines against various infectious diseases have utilized separate co-administration of αGalCer with the respective vaccine in order to harness its adjuvant activity. Gonzalez-Aseguinolaza G et al. (2002); Dondji B et al. (2008); Huang Y X et al. (2008); and Enomoto N et al. (2007). Thus, there remains a need for effective compositions and vaccines for enhancing immune responses to bacterial, e.g., mycobacterial, antigens.